1. Field of the Invention
The present invention relates to a method for treating autoimmune diseases, a screening method for a preventive or therapeutic agent for autoimmune diseases, and a diagnostic method for autoimmune diseases.
2. Background Art
Autoimmune diseases are pathological conditions caused by antibodies (autoantibodies) which are formed against components that constitute an individual's own body (autoantigens), or by T cells formed against such autoantigens. Various types of autoimmune diseases have been known: Some affect specific organs, and some others develop systemically. Autoantibodies provide a broad range of actions. Specifically, autoantibodies destruct cells (as in, e.g., autoimmune hemolytic anemia); impair physiological functions (as in, e.g., myasthernia gravis); excessively stimulate receptors (as in, e.g., Basedow's disease (Graves' disease)); or form antigen-antibody complexes (immune complexes) as deposits on the walls of blood vessels, to thereby cause inflammation (as in, e.g., systemic lupus erythematosus (SLE)). Usually, an individual does not immunologically respond to its own antigens; i.e., autoantigens (this mechanism is called self tolerance). However, according to current theory, when the self tolerance is lost for some reason, the individual develops an autoimmune disease. General causes of autoimmune diseases have not been elucidated. Therefore, symptomatic approaches have been major measures for treatment of autoimmune diseases, and practically, there is no well-established therapeutic method as yet.
Among other autoimmune disease, Sjögren's syndrome has been known to cause systematic chronic inflammation in exocrine glands of the whole body, including the lacrimal glands and the salivary glands, and which primarily involves dryness caused by functional deterioration of exocrine glands, as found in, for example, sicca syndrome associated with keratoconjunctivitis sicca or chronic sialadenitis. In addition to some hereditary factors, other factors such as immune disorders and unknown environmental factors are also believed to contribute to Sjögren's syndrome. However, details remain unknown, and thus, a need continues to exist for a radical, course-specific therapeutic method.
In one approach to elucidating the pathological causes of autoimmune diseases, researchers focus on the fact that most autoimmune diseases, including Sjögren's syndrome, develop primarily in menopausal or postmenopausal women. This suggests that estrogen deficiency causes some change in the target organs. In search for supportive evidence, the present inventor performed studies through use of mice suffering Sjögren's syndrome and reported that estrogen deficiency causes apoptosis of gland cells to thereby aggravate pathological conditions, and that through administration of estrogen, aggravation of the pathological conditions can be prevented (Ishimaru N, et al. Estrogen deficiency accelerates autoimmune exocrinopathy in murine Sjogren's syndrome through fas-mediated apoptosis, Am. J. Pathol. 155 (1), 173-81 (1999)).
RBAp48 (retinoblastoma associated protein 48) is a nucleoprotein which forms a complex with Rb protein (a known tumor suppressor gene product). Human RBAp48 gene was first obtained in 1993 (Qian Y W, et al. A retinoblastoma-binding protein related to a negative regulator of Ras in yeast, Nature 364 (6438), 648-52 (1993)). RBAp48 has been reported to form histone deacetylase complex to thereby participate in regulating cell differentiation or cell multiplication (Qian Y W, et al. Dual retinoblastoma-binding proteins with properties related to a negative regulator of ras in yeast, J. Biol. Chem. 270 (43), 25507-13 (1995); Nicolas E., et al. RBAp48 belongs to the histone deacetylase complex that associates with the retinoblastoma protein, J. Biol. Chem. 275 (13), 9797-804 (2000)). However, nothing has been known in relation to what effect RBAp48 exerts on improvement of pathological conditions of patients who suffer autoimmune diseases.
Accordingly, the present invention is directed to a method for treating autoimmune diseases, for which radical therapies have not yet been obtained; to a screening method for preventive or therapeutic agents for autoimmune diseases; and to a diagnostic method for autoimmune diseases.